SSRI Use in Anxiety Disorders

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Introduction   

Selective Serotonin Reuptake Inhibitors (SSRIs) are a medication class typically used to treat depression. SSRIs are considered first-line treatment for depression and other psychological disorders, including (2): 

• Major Depressive Disorder 
• Generalized Anxiety Disorder 
• Bulimia Nervosa 
• Bipolar Depression 
• Obsessive-Compulsive Disorder 
• Panic Disorder 

• Premenstrual Dysphoric Disorder 
• Treatment-Resistant Depression 
• Pot-traumatic Distress Disorder 
• Social Anxiety Disorder 

Additional disorders may be treated off-label, including (2): 

• Binge Eating Disorder 
• Body Dysmorphia Disorder 
• Fibromyalgia 
• Premature Ejaculation 
• Paraphilias 
• Autism 
• Raynaud’s Phenomenon 
• Vasomotor symptoms associated with menopause.  

SRRIs remain relatively safe, tolerable, and efficient in treating patients (2). 

Fluoxetine 

The Fluoxetine drug class includes brand names of Prozac, Rapiflux, Sarafem, and Selfemra 

(11). 

Indications 

Fluoxetine is an FDA-approved medication used to treat major depressive, obsessive-compulsive, binge eating, premenstrual dysphoric, and panic disorders. Fluoxetine is also prescribed for bulimia and bipolar depression.  

Off-label uses include social anxiety disorder, adult post-traumatic stress disorder (PTSD), borderline personality disorder, Raynaud phenomenon, and selective mutism (21). 

Mechanisms of Action and Pharmacokinetics 

Fluoxetine blocks the reuptake of serotonin into the presynaptic serotonin neurons. This is accomplished by blocking the reuptake transporter proteins located in the presynaptic terminal. There have been some indications of mild activity at the 5HT2A and 5HT2C receptors. Conversely, there is minimal activity on noradrenergic reuptake (21). 

Fluoxetine produces an activating effect that takes two to four weeks to see antidepressant effects. Fluoxetine actives norfluoxetine, a metabolite produced when cytochrome p450 enzyme acts on it. This indicates that fluoxetine has a high risk for drug-drug interactions that metabolize at the CYP2D6 isoenzyme (21). 

Fluoxetine has a half-life of two to four days. Fluoxetine’s active metabolite, norfluoxetine, has a longer half-life of seven to nine days (21). 

Contraindications and Precautions 

Fluoxetine is contraindicated in patients with (21): 

• Hypersensitivity to fluoxetine or its components 
• Use of monoamine oxidase inhibitors (MAOIs) to treat psychiatric disorders 
  • Prescribers should discontinue MAOIs for > 2 weeks before initiation of fluoxetine 
• Prescription of: 
  • Linezolid 
  • Pimozide 
  • Thioridazine 
  • Tamoxifen 
• History of seizures 
• Elderly patients 
• Suicidal thoughts or ideation 
  • Especially in pediatric patients or those aged 18 to 24 years old 
    • Monitor closely for the first two months of initiating therapy 
• During pregnancy 
  • Use in early pregnancy increases the risk of septal heart defects 
  • After 20 weeks, it is linked with a possible risk for pulmonary hypertension in newborns 
  • This may increase the risk of gestational hypertension and preeclampsia 
• Breastfeeding 
  • Trace amounts found in breast milk 

Precautions should be taken when prescribing Fluoxetine in patients with liver cirrhosis, as this diagnosis reduces clearance of fluoxetine and its active metabolite. This increases the elimination or half-life. Lower or less frequent doses should be considered for these patients (21). 

Adverse Effects and Black Box Warnings 

Fluoxetine’s most common side effects include (21): 

• Insomnia 
• Nausea 
• Diarrhea 
• Anorexia 
• Dry mouth 
• Headache 
• Drowsiness 
• Anxiety 
• Nervousness 
• Yawning 
• Decreased libido 
• Decrease arousal or lubrication 
• Bruising 
• Hyperhidrosis 
• Weight gain or loss 
• Decreased orgasm 
• Muscle weakness 
• Tremors 
• Pharyngitis 

Less common adverse effects include (21): 

• Bleeding 
• Seizures 
• Suicidal ideation and behaviors 
  • Especially in teenagers 

Most adverse effects will appear upon initiation of treatment and should fade with time. It is advised to wait for side effects to subside before changing treatment, as most side effects are dose- and time-dependent.  

If side effects continue after several weeks, dose adjustment then changing medication is recommended (21). 

If insomnia is present, patients should take medication in the early morning (21). 

A Black Box Warning is present for Fluoxetine, as this medication increases suicidal thoughts and behaviors. Individuals prescribed this medication should be closely monitored, especially teenagers as they are more prone to experiencing these severe adverse effects (5). 

Drug Interactions 

Fluoxetine interacts with several medications including (22): 

• Monoamine Oxidase inhibitors 
• Medications that increase serotonin levels 
  • Tricyclic antidepressants (TCAs) 
  • Lithium 
  • Triptan migraine medications 
  • Certain opioids 
  • Other SSRIs 
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs) 
• St John’s Wort 
• Medications that raise the risk of bleeding 
  • Warfarin 
  • Apixaban 
  • Rivaroxaban 
  • Clopidogrel 
  • Prasugrel 
• Pimozide and thioridazine 
• Medications metabolized by certain liver enzymes 
  • Flecainide 
  • Propafenone 
  • TCAs 
  • Benzodiazepines 
  • Antipsychotics 
  • Seizures 

Sertraline  

The Sertraline drug class includes the brand name: Zoloft (13). 

Indications 

Sertraline is FDA-approved to treat the following (20): 

• Major depressive disorder 
• Obsessive-compulsive disorder (OCD) 
• Panic disorder 
• Post-traumatic stress disorder (PTSD) 
• Premenstrual Dysphoric Disorder (PMDD) 
• Social Anxiety Disorder (SAD) 

Sertraline may be prescribed off-label for the following disorders (20): 

• Binge eating disorder 
• Body dysmorphic disorder 
• Bulimia Nervosa (BN) 
• Generalized Anxiety Disorder (GAD) 
• Premature ejaculation 

Mechanisms of Action and Pharmacokinetics 

Sertraline inhibits serotonin reuptake on the presynaptic terminals. This leads to an accumulation of serotonin, leading to better mood regulation, personality stability, and wakefulness or arousal (20). 

Sertraline has a half-life of 24 to 32 hours. Sertraline is metabolized by the liver (7). 

Contraindications and Precautions 

Sertraline is contraindicated in (20): 

• Patients with hypersensitivity to this drug or any of its components 
• Coadministration with: 
  • Thioridazine 
  • Pimozide 
  • Monoamine oxidase inhibitors  
    • Sertraline should not start <2 weeks of discontinuing any monoamine oxidase inhibitors, as this may lead to toxicity with serotonin syndrome.  
  • Serotonergic medication 
  • Disulfiram 
    • may cause an alcohol-disulfiram reaction. 

Adverse Effects and Black Box Warnings 

Sertraline has multiple adverse effects, including (20): 

• Syncope 
• Lightheadedness 
• Diarrhea 
• Nausea 
• Sweating 
• Dizziness 
• Xerostomia 
• Confusion 
• Hallucinations 
• Tremor 
• Somnolence 
• Impotence 
• Disorders of ejaculation 
• Fatigue 
• Rhinitis 
• Female sexual disorder 

More serious adverse effects include (20): 

• Prolonged QT interval 
• Inhibiting platelet aggregation, leading to bleeding risk 
• Serotonin syndrome, including symptoms of: 
  • Myoclonus 
  • Muscle rigidity 
  • Diaphoresis 
  • Tremor 
  • Hyperreflexia 
  • Agitated delirium 
  • hyperthermia 

Sertraline has a Black Box Warning related to increased risk of suicidal thoughts and ideation, particularly in pediatric patients and adult patients aged 18 to 24 (20). 

Drug Interactions 

Due to Sertraline’s interaction with many CYP enzymes, several drug-drug interactions are possible (7). These include: 

• Bepridil 
• Bromopride 
• Cisapride 
• Dronedarone 
• Eliglustat 
• Furazolidone 
• Iproniazid 
• Isocarboxazid 
• Levoketoconazole 
• Linezolid 
• Mesoridazine 
• Methylene Blue 
• Metoclopramide 
• Ozanimod 
• Phenelzine 
• Pimozide 
• Piperaquine 
• Procarbazine 
• Rasagiline 
• Safinamide 
• Saquinavir 
• Selegiline 
• Sparfloxacin 
• Terfenadine 
• Thioridazine 
• Toloxatone 
• Tranylcypromine 
• Ziprasidone 

Paroxetine  

The Paroxetine drug class includes brand names of Brisdelle, Paxil, and Pexeca (19). 

Indications 

Paroxetine is FDA-approved to treat the following disorders (19): 

• Major depressive disorder (MDD) 
• Obsessive-compulsive disorder (OCD) 
• Social anxiety disorder (SAD) 
• Panic disorder 
• Post-traumatic stress disorder (PTSD) 
• Generalized anxiety disorder (GAD) 
• Premenstrual dysphoric disorder (PMDD) 
• Vasomotor symptoms associated with menopause 

Paroxetine is prescribed off-label for the following disorders (19): 

• Obsessive-compulsive disorder (in children and adolescents) 
• Social anxiety disorder 
• Dysthymia 
• Body dysmorphic disorder 
• Postpartum depression 
• Premature ejaculation 
• Malignancy related to pruritus 
• unresponsive to standard treatment 

Mechanisms of Action and Pharmacokinetics 

Paroxetine blocks the serotonin reuptake transports (SERT), increasing the concentration of synaptic serotonin. The diminished serotonin concentration induces the upregulation of serotonergic receptors. Paroxetine induces the downregulation of upregulated serotonin receptors to balance the receptor concentration.  

Paroxetine has also shown some affinity for muscarinic, adrenergic (alpha and beta), dopaminergic (D2), serotonergic (5-HT2), and histaminergic (H1) receptors – which assist with antidepressant effects (19). 

Paroxetine is metabolized via hepatics CYPP450 2D6 and has a half-life of approximately 21 hours (19). 

Contraindications and Precautions 

Paroxetine is contraindicated in the following situations (19): 

• Concurrent use: 
  • Monoamine oxidase inhibitors (MAOIs) 
    • Causes serotonin syndrome 
  • Thioridazine 
    • Causes cardiac arrhythmias 
  • Pimozide 
    • Causes serotonin syndrome 

Precautions should be taken when prescribing paroxetine with (19): 

• Tricyclic antidepressant (TCA) use 
  • Inhibits TCA metabolism 
• Tamoxifen use 
  • Inactivates tamoxifen 
• Any drugs affecting hepatic metabolism 
• Pregnant or breastfeeding patients 
  • Increased risk of cardiovascular malformations in the first trimester 

Adverse Effects and Black Box Warnings 

Paroxetine has dose-dependent side effects. The most common side effects include (19):  

• Alopecia 
• Apathy 
• Chest pain  
• Constipation 
• Diarrhea 
• Dizziness 
• Drowsiness 
• Dry mouth 
• Eczema 
• Edema  
• Headache 
• Hypomania 
• Hyponatremia 
• Loss of appetite 
• Mania 
• nausea 
• Palpitations 
• Photosensitivity 
• Sexual side effects 
• Sleep disturbance 
• Sweating 
• Tachycardia 
• Tremor 
• Vasodilation 
• Weight gain 

Discontinuation syndrome is more severe with Paroxetine versus other SSRIs. Withdrawal may occur, and symptoms include (19): 

• Dizziness 
• Lethargy 
• Nausea 
• Vomiting 
• Headache 
• Fever 
• Chills 
• Vivid dreams 
• Electric shock-like sensations 
• Dyskinesia 
• Anxiety 
• Crying 
• Irritability 
• Depersonalization 

A Black Box Warning is present for Paroxetine related to increased suicidal thoughts and behaviors. Anyone under the age of 24 has a higher risk for these serious adverse effects and should be carefully considered and monitored when prescribed (9). 

Drug Interactions 

Drug-drug interactions for Paroxetine include (19): 

• Monoamine oxidase inhibitors (MAOIs) 
• Thioridazine 
• Pimozide 
• Tricyclic Antidepressant (TCA) 
• Tamoxifen use 
• Any drugs affecting hepatic metabolism 

Fluvoxamine  

The Fluvoxamine drug class includes the brand names Luvox and Luvox CR (16). 

Indications 

Fluvoxamine is FDA-approved to treat the following disorders (1): 

• Obsessive-compulsive disorder (OCD) 
• Depression 
• Social anxiety disorder 

Fluvoxamine has recently been prescribed off-label for the treatment of COVID-19. However, the COVID-19 Treatment Guidelines Panel recommends against it. There is insufficient evidence for the use of fluvoxamine in combination with inhaled budesonide for non-hospitalized patients.  

Conversely, patients with are receiving fluvoxamine for underlying treatments should continue therapy if diagnosed with COVID-19 (16). 

Mechanisms of Action and Pharmacokinetics 

Fluvoxamine blocks the reuptake of serotonin at the sodium-dependents serotonin reuptake transports (SERT). This enhances the action of serotonin on the 5HT1A auto receptors, leading to an increase in the concentration of synaptic serotonin (16). 

Fluvoxamine is metabolized by the liver and has a half-life of 12 to 15 hours (4). 

Contraindications and Precautions 

Fluvoxamine is contraindicated in the following situations (16): 

• Concurrent use of: 
  • Ethanol 
  • Tobacco 
• Comorbidities, as this medication may impact the illness or medications to treat: 
  • Bipolar disorder 
  • Bleeding problems 
  • Depression 
  • Glaucoma 
  • Heart-attack 
  • Heart disease 
  • Heart rhythm problems 
  • Hyponatremia 
  • Mania 
  • Mental health problems 
  • Seizures 
  • Liver disease 

Precautions should be taken when prescribing Fluvoxamine to (16): 

• Patients who drink or have a history of alcoholism 
• Patients with vocations that include operating heavy machinery 
• May cause drowsiness 
• Patients with bleeding problems 
• This medication may increase the risk for bleeding 
• Patients who are expecting or trying to conceive 
• There is some link between this medication and infertility 

Adverse Effects and Black Box Warnings 

Fluvoxamine has the following side effects include (16): 

• More common side effects include: 
  • Sexual side effects 
  • Decreased libido, erectile dysfunction 
• Less common side effects include: 
  • Changes to behavior or mood 
  • Decreased orgasm 
  • Difficulty breathing 
  • Difficulty urinating 
  • Twitching  
• Rare 
  • Agitation 
  • Blurred vision 
  • Chills 
  • Clumsiness 
  • Confusion 
  • Diarrhea 
  • Fever 
  • Inability to move eyes 
  • Decreased or increased ability to move the body 
  • Menstrual changes 
  • Nosebleeds 
  • Overactive reflexes 
  • Poor coordination 
  • Red or irritated eyes 
  • Skin issues include:  
    • Redness 
    • Tenderness 
    • Itching 
    • Burning 
    • Peeling 
  • Restlessness 
  • Seizures 
  • Shivering 
  • Skin rash 
  • Sore throat 
  • Sweating 
  • Excitement that cannot be controlled 
  • Trembling or shakiness 
  • Unusual bruising 
  • Unusual or sudden body or facial movements 
  • Unusual secretion of milk in females 
  • weakness 

A Black Box Warning is present for Fluvoxamine related to increased suicidal thoughts and behaviors (6). 

Drug Interactions 

Drug-drug interactions for Fluvoxamine include (16): 

• Alosetron 
• Pimozide 
• Ramelteon 
• Thioridazine 
• Tizanidine 
  • Increase side effects 
• Monoamine oxidase inhibitors (MAOIs) 
  • Should not take until MAOIs are discontinued for > 2 weeks 
• Linezolid 
• Methylene blue injection 
• Phenelzine 
• Selegiline 
• Tranylcypromine 
• Buspirone 
• Fentanyl 
• Lithium 
• Tryptophan 
• St John’s Wort 
• Amphetamines 
• Some pain medications 
• Blood thinners 

Citalopram 

The Citalopram drug class includes the brand name of Celexa (11). 

Indications 

Citalopram is FDA-approved to treat the following disorders (11): 

• Depression in adults 

Citalopram is prescribed off-label to treat: 

• Obsessive-compulsive disorder (OCD) 
• Panic disorder 
• Generalized anxiety disorder (GAD) 
• Social anxiety disorder (SAD) 
• Premenstrual dysmorphic disorder (PMDD) 
• Binge eating disorder 
• Posttraumatic stress disorder (PTSD) 
• Premature ejaculation 
• Poststroke depression 

Mechanisms of Action and Pharmacokinetics 

Citalopram escalates the brain-derived neurotrophic factor (BDNF) in the hippocampus and preferential cortex, which can be decreased in patients with depression (18). 

Citalopram is metabolized by the liver and has a half-life of 24 to 48 hours. This may take longer due to hepatic impairment (18). 

Contraindications and Precautions  

Citalopram is contraindicated in (18): 

• Concomitant use of: 
• monoamine oxidase inhibitors (MAOIs) 
• Serotonin syndrome, including symptoms of: 
  • Myoclonus 
  • Muscle rigidity 
  • Diaphoresis 
  • Tremor 
  • Hyperreflexia 
  • Agitated delirium 
  • Hyperthermia 
• Urokinase 
  • Pimozide 
  • Methylene blue 
  • Linezolid 
  • Dapoxetine 
• Hypersensitivity to the drug or excipient 
  • Increases thioridazine concentrations 
    • Lead to dangerous arrhythmias 

Adverse Effects and Black Box Warnings 

Adverse effects of Citalopram include (18): 

• Most common 
  • Drowsiness 
  • Insomnia 
  • Dizziness 
  • Headache (dose-dependent) 
  • Diaphoresis 
  • Nausea 
  • Vomiting 
  • Xerostomia 
  • Constipation 
  • Diarrhea 
  • Ejaculation disorder (dose-dependent) 
• Less common 
  • Myocardial infarction 
  • Prolonged QT interval 
  • Torsades de pointes 
  • Hemorrhage 
  • Cerebrovascular accident 
  • Suicidal ideation 
  • Manic 
  • Serotonin syndrome 

Citalopram has a Black Box Warning related to increased risk of suicidal thoughts and ideation, particularly in pediatric patients and adult patients aged 18 to 24 (18). 

Drug Interactions 

Citalopram interactions significantly with the following medications, and should be monitored closely (18): 

• Bupropion 
• Omeprazole 
• Esomeprazole 
• Cimetidine 
• Fexinidazole 
• Voriconazole 
• Fluoxetine 
• Fluvoxamine 
• Fluconazole 

Escitalopram 

The Escitalopram drug class includes the brand name Lexapro (14). 

Indications 

Escitalopram is FDA-approved to treat the following disorders (8): 

• Depressive disorder in adults and adolescents, ages 12-17 
• Generalized anxiety disorder for adults and children, ages7+ 

Escitalopram is prescribed off-label for (8): 

• Social anxiety disorder 
• Obsessive-compulsive disorder 
• Panic disorder 
• Posttraumatic disorder 
• Premenstrual dysphoric disorder 
• Vasomotor symptoms associated with menopause 

Mechanisms of Action and Pharmacokinetics 

Escitalopram binds to the sodium-dependent serotonin transporter protein (SERT) in the presynaptic neuron. This inactivates the SERT and causes an elevation in the synaptic serotonin levels (8). 

Escitalopram is metabolized by the liver and has a half-life of 27 to 33 hours (8). 

Contraindications and Precautions 

Escitalopram is contraindicated in the following situations (8): 

• Hypersensitivity to the medication or any of its components 
• Concurrent use of: 
  • MAOIs 
  • pimozide 
• QT prolongation 
  • Or family history 

Precautions should be taken when prescribing Escitalopram, including assessment and reduction of risk for serotonin syndrome. Medications that should be avoided to prevent this include (8): 

• Other antidepressants 
• Triptans 
• Fentanyl 
• Lithium 
• Tramadol 
• Tryptophan 
• Buspirone 
• Amphetamines 
• St John’s Wort 
• Methylene blue 
• Linezolid 
• MAOIs
   

  If possible, obtaining genetic testing for patients before prescribing could show an individual’s enzyme activity. If the patient is classified as a poor metabolized of the enzyme, CYP2C19, they are at a greater risk for drug reactions and may want to reduce the dose or consider alternative treatment (8) 

   

  Adverse Effects and Black Box Warnings 

  Escitalopram has the following side effects include (8): 

• Insomnia 
• Sexual dysfunction 
  • Reduce libido 
  • Anorgasmia 
  • Male ejaculatory delay 
• Nausea 
• Increased sweating 
• Fatigue 
• Somnolence 
• QT prolongation 
• Serotonin syndrome 
  • Rare but serious 

A Black Box Warning is present for Escitalopram for increased risk of suicidal ideation. Patients should be closely monitored for behavioral changes or destructive behaviors, particularly in pediatric and adolescent patients (8). 

Drug Interactions 

Drug-drug interactions for Escitalopram include (8): 

• Rasagiline 
  • Serotonin syndrome risk 
• Antiplatelet agents 
  • Increased risk for bleeding 
• NSAIDS 
  • Upper GI bleeding risk 
• Aspirin or dual antiplatelet therapy 
  • Risk of bleeding 
• Other agents that prolong QTc intervals 
  • Amiodarone 
    • Especially in patients with chronic kidney disease 

Vilazodone 

The Vilazodone drug class includes the brand name Viibryd (3). 

Indications 

Vilazodone is FDA-approved to treat the following disorders (3): 

• Depression 

Mechanisms of Action and Pharmacokinetics 

Vilazodone binds to the sodium-dependent serotonin transporter protein (SERT) in the presynaptic neuron. This inactivates the SERT and causes an elevation in the synaptic serotonin levels (17). 

Vilazodone is metabolized by the liver and has a half-life of 25 hours (17). 

Contraindications and Precautions 

Vilazodone is contraindicated in the following situations (23): 

• Concurrent use of: 
  • MAOIs 
  • Methylene blue 
    • Must be discontinued > 14 days before starting Vilazodone 

Precautions should be taken when prescribing Vilazodone for patients at risk for (23): 

• Suicidal thoughts 
• Bleeding risk 
• Fractures 
• Ocular issues 
• Serotonin syndrome 
• Sexual dysfunction 
• SIADH and hyponatremia 
• Mania/hypomania 
• Seizure disorder 

This medication also poses a risk of discontinuation syndrome and should only be stopped under the direction of a provider throughout monitored time (23). 

Adverse Effects and Black Box Warnings 

Vilazodone has the following side effects include (3): 

• Allergic reaction 
• Bleeding 
• Irritability 
• Confusion 
• Irregular heartbeat 
• Muscle stiffness 
• Sweating high fever 
• Seizures 
• Chills  
• vomiting  
• diarrhea 
• fatigue 
• dizziness 
• headache 
• sudden eye pain 
• changes in vision 
• suicidal ideation 
• change in sex drive or performance 
• dry mouth 
• trouble sleeping 

A Black Box Warning is present for Vilazodone 

Drug Interactions 

Drug-drug interactions for Vilazodone include (3): 

• Linezolid 
• MAOIs 
• Methylene blue 
• Amphetamines 
• Aspirin 
• Buspirone 
• Diet medications 
  • Dexfenfluramine 
  • Fenfluramine 
  • Phentermine 
  • Sibutramine 
• Headache medications 
  • Almotriptan 
  • Eletriptan 
  • Frovatriptan 
  • Naratriptan 
  • Rizatriptan 
  • Sumatriptan 
  • Zolmitriptan 
• Blood clots medications 
  • Warfarin 
  • Enoxaparin 
  • Daletparin 
• Infection treatment 
  • Clarithromycin 
  • Itraconazole 
  • Voriconazole 
  • Ketoconazole 
  • Rifampin 
• Seizure medications 
  • Carbamazepine 
  • Phenytoin 
• Digoxin 
• Fentanyl 
• Lithium 
• NSAIDS 
• Other antidepressants 
• St John’s Wort 
• Tramadol 

Conclusion

Selective Serotonin Reuptake Inhibitors (SSRIs) are a medication class typically used to treat depression. SSRIs are considered the first-line treatment for depression and other psychological disorders. However, many SSRIs can be used to treat various anxiety disorders.  

Some of the SSRIs are FDA-approved for the treatment of anxiety, while others the provider may prescribe off-label if circumstances permit. While SRRIs remain relatively safe, tolerable, and efficient in treating patients. providers should pay special attention to serious or life-threatening side effects of SSRIs including suicidal ideation, discontinuation syndrome, serotonin syndrome, prolonged QTc interval, and increased risk for bleeding (2). 

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